A precision counterstrike on central nervous system autoimmunity

Autoantibodies targeting the N-methyl-D-aspartate receptor (NMDAR) induce debilitating neuropsychiatric symptoms and potentially fatal complications due to brain swelling and autonomic instability, requiring aggressive treatments to eliminate the autoreactive B-cells and autoantibodies causing disease.In a recent Cell paper, Reincke et al. genetically engineer T-cells to express an autoantigen-based chimeric autoantibody receptor (CAAR) to direct T-cell cytotoxicity specifically against anti-NMDAR B-cells, establishing the basis for a novel precision cellular immunotherapy for NMDAR encephalitis.N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common of the autoimmune encephalitides, often presenting in children and young adults with dyskinesia, seizures, agitation, hallucinations, or catatonia.Autoantibodies target the NMDAR GluN1 subunit, leading to decreased synaptic NMDAR density.Therapy aims to suppress or eliminate B-cells or autoantibodies with corticosteroids, intravenous immunoglobulin, plasmapheresis, rituximab, and/or cyclophosphamide.B-cell depletion with rituximab decreases rates of disease relapse and improves symptoms, although repeated infusions are needed to maintain disease control and can lead to serious infections, highlighting the need for better and safer therapies.Toward this end, Reincke and co-authors designed chimeric autoantibody receptors (CAARs) with ectodomains comprising the main immunogenic region of the NMDAR GluN1 subunit (Fig. 1a), either as the GluN1 amino-terminal domain (ATD) alone (N1 ATD ), or all GluN1 extracellular domains, or N1 ATD in tandem with GluN2B-ATD (Fig. 1b). 1 The NMDAR-CAAR ectodomain targets the anti-NMDAR B cell receptor (BCR), a membrane-bound autoantibody that marks the autoreactive B-cell population in NMDAR encephalitis.Upon target BCR engagement, the CAAR 4-1BB costimulatory and CD3ζ cytoplasmic domains direct NMDAR-CAAR T-cell (NMDAR-CAART) proliferation and cytolysis of NMDARspecific B-cells, sparing healthy B-cells that do not express anti-NMDAR BCRs (Fig. 1c).To better understand the autoreactive B-cells targeted by NMDAR-CAART, the authors first characterized epitopes recognized by serum IgG and recombinant mAbs cloned from patients with NMDAR encephalitis.Patient serum IgG and mAb binding to N1 ATD N2B ATD -CAAR is greater than to N1 ATD -CAAR alone, suggesting that NMDAR autoantibodies bind a quaternary epitope at the GluN1-GluN2B interface or N1 ATD epitopes stabilized by N2B ATD .Accordingly, N1 ATD N2B ATD NMDAR-CAART killed a broader range of